This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The simian lentivirus SIVsmmFGb induces neurological disease in 90 [unreadable]100% of infected pigtailed macaques and is a reliable model of HIV infection of the central nervous system (CNS). Little is understood about how colonization of the CNS during the early stages of infection, and subsequent host adaptive immune responses, affect the genetic diversity of this virus. Also unknown is whether SIVsmmFGb forms distinct genetic compartments between CNS tissues during early infection and whether these genetic compartments remain following the onset of host adaptive immune responses. The initial seeding of the CNS reduced the genetic diversity of the Env V1 region and Int, but had less of an effect on Nef. Host adaptive immunity altered the genetic diversity of the Env V1 region and Int in all tissues, but results were more variable for Nef. Following initial seeding of the CNS, SIVsmmFGb env V1 region, nef and int sequences each formed distinct genetic compartments between most of the CNS tissues studied, compartments that remained largely unchanged with the onset of adaptive immunity. Formation of env V1 region compartments during initial seeding of the CNS was due to positive selection, while negative selection drove formation of the nef and int compartments. Selection continued through the adaptive immune response, with selective pressure increasing on all three genes in some CNS tissues. Over the course of infection, the env V1 regions in most compartments underwent convergent evolution, with similar results for nef. Conversely, int underwent divergent evolution in most compartments. Functional differences in env V1 region and int between compartments decreased over the course of infection, while nef functional differences between compartments saw a net increase. Our results provide insight into lentivirus seeding and evolution in the CNS that may be applicable to similar processes in HIV infection.